The long term goal of this Program is to induce and maintain immunologic tolerance to organ allografts. Synthetic peptides corresponding to structural regions of HLA class I molecules induce T cell unresponsiveness in vitro and can prevent transplant rejection in some animal models. The studies proposed in Project 2 are based on the finding that a synthetic peptide corresponding to residues 65-79 of the alpha chain of the HLA class II molecule DQA03011 inhibits T cell cytotoxicity and proliferation. Inhibition is not allele specific, but involves cell cycle associated molecules. In aim 1, fluorescence and confocal microscopy will be used to determine the subcellular localization of this peptide in cells. The effect of the peptide on cell cycle associated kinases and other molecules will be assessed. In aim 2, the receptor for the peptide will be identified and characterized. Two approaches will be used: biochemical purification using derivatized peptide and genetic selection using the yeast two hybrid system. In aim 3, the in vivo effects of the peptide will be evaluated in three different animal models: heterotopic heart transplantation, graft versus host disease, and diabetes mellitus in the NOD mouse. This project interacts with Project 1, which investigates similar questions for the class I peptide, and Project 3, which uses retroviral vectors to deliver peptides in vivo.